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We have reported that the radical scavenger XJB-5-131 attenuates or reverses progression of the disease phenotype in the  HdhQ(150/150)  mouse, a slow onset model of HD. Here, we tested whether XJB-5-131 has beneficial effects in  R6/2  mice, a severe early onset model of HD. We found that XJB-5-131 has beneficial effects in  R6/2  mice, by delaying features of the motor and histological phenotype. The impact was sex-dependent, with a stronger effect in male mice. XJB-5-131 treatment improved some locomotor deficits in female  R6/2  mice, but the effects were, in general, greater in male mice. Chronic treatment of male  R6/2  mice with XJB-5-1-131 reduced weight loss, and improved the motor and temperature regulation deficits, especially in male mice. Treatment with XJB-5-131 had no effect on the lifespan of  R6/2  mice. Nevertheless, it significantly slowed somatic expansion at 90 days, and reduced the density of inclusions. Our data show that while treatment with XJB-5-131 had complex effects on the phenotype of  R6/2  mice, it produced a number of significant improvements in this severe model of HD.

XJB-5-131-mediated improvement in physiology and behaviour of the R6/2 mouse model of Huntington's disease is age- and sex- dependent